SUMMARY Millions of blood samples are tested annually to establish blood type compatibility between blood donors and transfusion recipients. However, current testing methods are encumbered by the need for large blood samples, transportation to centralized laboratories, time to centrifuge and perform testing, specialized reagents, and technical training needs, placing a costly burden on the medical system. In particular, reduced blood sampling volumes are desirable to avoid exacerbating anemia in patients who may require transfusion, particularly pediatric and critically ill patients. Additionally, current test times create the need to maintain universal units to provide emergency transfusions when the blood type of the patient is not yet known, placing a strain on the blood supply. Thus, there is a need for smaller, faster, better, and cheaper blood group testing. Our proposed solution will perform blood group testing on a multiplexed, low-cost, and scalable silicon nanophotonic biochip. This technology has been demonstrated in proof-of-concept studies to detect A, B, and RhD (D) blood groups and anti-A and anti-B antibodies in small volume blood samples. SiDx, Inc. has licensed the core intellectual property, engaged an experienced FDA regulatory consultant, and secured seed funding to commercialize this technology. This application is seeking SBIR support for SiDx to advance this blood group testing technology towards readiness for FDA studies, with the future goal of FDA regulatory approval and commercialization of the product as a medical diagnostic. In this SBIR Fast Track Phase I/II application, we propose specific aims for each of the two Phases: In Phase I we propose one aim: to develop proof-of-concept assays to functionalize silicon photonic biosensors for the detection of blood groups C, E, and K. These blood groups are critical minor blood group antigens that can provoke severe, potentially life-threatening immune reactions and bring value in expanding the multiplexed blood group testing capabilities of the future product. In Phase II, we propose 2 aims: Aim II.1: to study surface functionalization conditions and optimize surface capture of streptavidin via covalent (silane) and non-covalent (physisorption) means on silicon photonic surfaces for blood group antigen and antibody assay validation; and Aim II.2: to multiplex ABO, D, C, E, and K blood group assays (and controls) on optimized functional surfaces using an inkjet arrayer and test assay performance. This aim will also assess samples that can challenge conventional testing methods in the clinical laboratory, such as weak D and mixed field reactions This silicon photonic blood typing chip holds the promise to modernize blood group testing with simple, fast, fully automated multiplexed blood group testing in small volume blood samples. We predict that, if successful, this product holds the potential to transform both blood group testing and transfusion medicine through small sample volume requirements, fully automated testing, and rapid time to results. This should reduce iatrogenic blood loss, delays in transfusion, minimize the use of universal units, and improve access in hospitals that currently have limited resources to support blood group testing capabilities.